Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan)

Angiotensin-converting enzyme inhibitors (ACEi) have been a cornerstone treatment for
patients with heart failure and reduced ejection fraction (HFrEF) for over 25 years. They are
included in every major set of guidelines for HFrEF management. Angiotensin receptor blockers
(ARB's, such as valsartan) have similarly been shown to decrease the mortality rate of
patients with HFrEF for patients who are unable to tolerate ACEi therapy.

The newest neurohormonal therapy approved for heart failure (August 2015) is
sacubitril/valsartan (trade name Entresto). This medication is the first of a new family of
agents (ARNI = angiotensin receptor antagonist with neprilysin inhibitor), combining the
approved angiotensin receptor blocker valsartan with sacubitril, an inhibitor of neprilysin,
which is a neutral endopeptidase that degrades endogenous vasoactive peptides. Treatment with
sacubitril increases circulating levels of natriuretic peptides, which have been shown to
facilitate natriuresis and vasodilation. Although the precise mechanisms responsible for
benefit in heart failure remain unclear, sacubitril/valsartan may reduce the fluid retention
and vasoconstriction that contribute to heart failure symptoms, and may also decrease
apoptosis and remodeling that lead to disease progression. There is limited data about the
incremental acute and long-term hemodynamic effects of composite
neprilysin/angiotensin-receptor inhibitors over enalapril, and these data may provide
important mechanistic insights.

Progress in HF management outside the hospital has included validation of a strategy of
ongoing monitoring of pulmonary artery pressures every day from home via a monitor implanted
in a distal pulmonary artery, the CardioMEMS device. The information is transmitted to a
website where it is reviewed by the HF team, who can intervene to adjust diuretics and other
medications by phone to avert decompensation and re-hospitalization. The device received FDA
approval in mid 2014, and is now being implanted in many cardiac catheterization
laboratories, including at Brigham and Women's Hospital. The pressure information is reviewed
regularly by the HF management team who are in regular contact with the patient to aid in
management decisions.

In summary, this pilot study will assess the impact of sacubitril/valsartan, an approved drug
for heart failure with reduced ejection fraction (HFrEF) on the elevated pulmonary artery
pressures measured using an implanted monitoring device that is also approved for such
patients. Both the medication and the device will be used according to approved indications.

Inclusion Criteria:

1. Patients able to provide written informed consent

2. Patients ≥18 years of age, male or female, in NYHA Class II- III HF, previously
hospitalized for HFrEF with LVEF < 35% (measured within the past year), and who have
no subsequent LVEF>35%.

3. Systolic BP > 95 mm Hg at most recent clinical assessment.

4. Stable, ambulatory patients without the need for change in diuretics and other HF
drugs (RAS blockers, beta blockers or mineralocorticoid receptor blockers) during the
past 5 days

5. CardioMEMS HF System implanted for NYHA Class III HF. Patient transmitting information
regularly and system functioning appropriately.

6. NT-proBNP > 500 pg/ml within 90 days of CardioMEMS implantation.

7. Average PAPm >20mm Hg during the 7 days prior to enrollment, including at least 4
daily measurements.

8. Women of childbearing age must be on highly effective method of contraception

Exclusion Criteria:

1. Treatment with vasodilators (other than nitrates, hydralazine) and/or IV inotropic
drugs.

2. Entresto taken within the past 30 days.

3. History of hypersensitivity, intolerance or angioedema to previous renin-angiotensin
system (RAS) blocker, ACE inhibitor, ARB, or Entresto.

4. eGFR < 30 ml/min/1.73 m2 as measured by the simplified MDRD formula.

5. Serum potassium > 5.5 mmol/L.

6. Acute coronary syndrome, stroke, transient ischemic attack, cardiovascular surgery,
PCI, or carotid angioplasty within the preceding 3 months.

7. Coronary or carotid artery disease likely to require surgical or percutaneous
intervention within 3 months after trial entry.

8. Non-cardiac condition(s) as the primary cause of dyspnea.

9. Implantation of a cardiac resynchronization therapy device (CRT/D) within the pr
preceding 3 months or intent to implant a CRT/D, which may alter the pressures during
the course of the study.

10. History of heart transplantation, placement of an LVAD, listing for Status IA for
cardiac transplantation or planned placement of an LVAD within 3 months following
randomization.

11. Documented untreated ventricular arrhythmia with syncopal episodes within the prior 3
months.

12. Symptomatic bradycardia or second or third degree heart block without a pacemaker.

13. Hepatic dysfunction, as evidenced by total bilirubin > 3 mg/dl.

14. Pregnancy

15. Women who are breastfeeding

16. Chronic lithium use